15-48340956-C-T

Variant names:

• chr15-48340956-C-T
• rs11637235
• NM_001025248.2:c.557-333C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001025248.2(DUT):​c.557-333C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 152,112 control chromosomes in the GnomAD database, including 28,323 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (28323 hom., cov: 32)
• Consequence: DUT NM_001025248.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.892
• Publications: 28 publications found

Genes affected

DUT (HGNC:3078): (deoxyuridine triphosphatase) This gene encodes an essential enzyme of nucleotide metabolism. The encoded protein forms a ubiquitous, homotetrameric enzyme that hydrolyzes dUTP to dUMP and pyrophosphate. This reaction serves two cellular purposes: providing a precursor (dUMP) for the synthesis of thymine nucleotides needed for DNA replication, and limiting intracellular pools of dUTP. Elevated levels of dUTP lead to increased incorporation of uracil into DNA, which induces extensive excision repair mediated by uracil glycosylase. This repair process, resulting in the removal and reincorporation of dUTP, is self-defeating and leads to DNA fragmentation and cell death. Alternative splicing of this gene leads to different isoforms that localize to either the mitochondrion or nucleus. A related pseudogene is located on chromosome 19. [provided by RefSeq, Jul 2008]

DUT Gene-Disease associations (from GenCC):

• bone marrow failure and diabetes mellitus syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUT	NM_001025248.2	c.557-333C>T		intron_variant	Intron 4 of 6	ENST00000331200.8	NP_001020419.1
DUT	NM_001330286.2	c.302-333C>T		intron_variant	Intron 4 of 6		NP_001317215.1
DUT	NM_001948.4	c.293-333C>T		intron_variant	Intron 3 of 5		NP_001939.1
DUT	NM_001025249.1	c.224-333C>T		intron_variant	Intron 4 of 6		NP_001020420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUT	ENST00000331200.8	c.557-333C>T		intron_variant	Intron 4 of 6	1	NM_001025248.2	ENSP00000370376.2

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81753 AN: 151994 Hom.: 28329 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.721

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.00828

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.568

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.537 AC: 81730 AN: 152112 Hom.: 28323 Cov.: 32 AF XY: 0.535 AC XY: 39773 AN XY: 74356

African (AFR) AF: 0.152 AC: 6315 AN: 41496

American (AMR) AF: 0.500 AC: 7626 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2722 AN: 3472

East Asian (EAS) AF: 0.00849 AC: 44 AN: 5180

South Asian (SAS) AF: 0.530 AC: 2554 AN: 4818

European-Finnish (FIN) AF: 0.759 AC: 8030 AN: 10582

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.771 AC: 52388 AN: 67982

Other (OTH) AF: 0.561 AC: 1183 AN: 2110

Alfa AF: 0.685 Hom.: 159591

Bravo AF: 0.498

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.49
DANN	Benign	0.73
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11637235; hg19: chr15-48633153;